We demonstrated that hyperbaric oxygen (HBO) treatment of rabbits fed a cholesterol-rich diet dramatically reduces atherosclerosis and accelerates the regression of existing lesions. Our preliminary studies extend this model to the apoE/LDLR double KO and apoE KO mice. A 10-week regimen of HBO treatment of female apoE KO mice dramatically decreases (by >70%) the extent of lesion formation in the aortic root and arch. These changes are accompanied by significant increases in the expression of antioxidant enzymes (ecSOD, Mn-SOD, PON1) in the liver, peritoneal macrophages (ecSOD and GPX3) and the aortic tissue (ecSOD and GPX3). Moreover, HBO treatment also significantly stimulates IL-10 and inhibits IL-12 secretion, greatly altering the ratio of the two cytokines. We also observed a significant decrease in spleen size and a profound (>95%) decrease in delayed hypersensitivity to oxLDL, as a result of HBO treatment, suggesting that this treatment also targets the immune system. Based on these observations the experiments proposed in this application are designed to test the hypotheses that HBO treatment induces, in the vessel wall (aorta), multiple anti-oxidant enzymes and suppresses the generation of reactive oxygen species. HBO treatment has also an immunosuppressive effect: a direct effect on the lymphocyte population (alteration of the Th1/Th2 ratio) to an anti-atherogenic phenotype (Th2 dominant response); and an indirect effect by suppressing the formation of oxidized antigen formation (oxLDL and lipid peroxides). The proposed studies will examine the effects of a standard HBO regimen on key target enzyme and cytokine expression by real-time RT-PCR and western blots as well as activity assays, as appropriate, and the extent of lesion formation. We will also examine the effect of HBO treatment on lung and spleen lymphocyte populations and examine the effect of specific T cell adoptive transfers on lesion development. Finally, we will examine the kinetics of key target enzyme and cytokine induction/suppression and changes in the immune response following an acute as well as multiple exposures to HBO. Ultimately, HBO treatment may provide a non-invasive and effective alternative to patients at risk for coronary heart disease.